Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase
Date of Original Version
Protein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2), The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site. © 2006 American Chemical Society.
Publication Title, e.g., Journal
Journal of Medicinal Chemistry
Gu, Xianfeng, Yuehao Wang, Anil Kumar, Guofeng Ye, Keykavous Parang, and Gongqin Sun. "Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase." Journal of Medicinal Chemistry 49, 25 (2006). doi: 10.1021/jm061058c.